Prostate cancer is the most common malignancy diagnosed in males and a leading cause of mortality in western countries (American Cancer Society, 2010 (http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-026238.pdf)). Androgens and stimulation of their receptor, androgen receptor (AR), are essential for the development and function of the normal prostate gland, and the development and progression of prostate cancer (reviewed in Basu S et al., Horm Cancer. 2010 October; 1(5):223-8.; Yadav N et al., Minerva Urol Nefrol. 2012 March; 64(1):35-49). For metastatic prostate cancer, androgen deprivation therapy remains the standard treatment. Despite the fact that initially more than 90% of patients respond to androgen deprivation therapy, the clinical benefits are temporary with tumors becoming refractory and progressing to androgen-independent/castration-resistant prostate cancer (CRPC) (Rini B I et al., Curr Treat Options Oncol. 2002 October; 3(5):437-46.; Carles J et al., Clin Transl Oncol. 2012 March; 14(3):169-76). CRPC is associated with continued androgen receptor (AR) activation despite hormonal castration and/or treatment with currently available anti-androgens. The molecular mechanism of androgen stimulation of prostate cancer growth and the switch to androgen independence is not fully clear. The progression to androgen independence may be explained by changes with the androgen receptor, such as amplification, mutations, or altered activity of splice variants. Other possible mechanisms include tumor cell autonomous production of androgens, ligand-independent activation of AR by kinases like ERK or AKT (reviewed in Dutt S S et al., Future Oncol. 2009 November; 5(9):1403-13. and Attar R M et al., Clin Cancer Res. 2009 May 15; 15(10):3251-5) or that androgens may regulate prostate cancer proliferation by up-regulating autocrine loops involving peptide growth factors and their cognate receptors (De Bellis A et al., J Clin Endocrinol Metab 1996; 81:4148-54.). All these mechanisms could result in independence to endocrine androgens.
Benign prostatic hyperplasia (BPH) can be detected in the vast majority of men as they age (Parsons J K., Curr Bladder Dysfunct Rep. 2010 December; 5(4):212-218). BPH can be defined as a non-cancerous enlargement of the prostate resulting from a proliferation of both benign stromal, and to a lesser extent, epithelial cells (Foster C S. Prostate 2000; 9:4-14.). In both of these cell types, dihydrotestosterone (DHT), a metabolite of testosterone that is 10 times more potent because it dissociates from the androgen receptor more slowly than testosterone, binds to nuclear androgen receptors resulting in the transcription of growth factors that are mitogenic to the epithelial and stromal cells. In the prostate, testosterone is converted to DHT by the enzyme 5α-reductase, type 2. In the condition of BPH, local testosterone levels can be elevated more than 100-fold above serum levels leading to an increased availability of DHT (Gat Y et al., Andrologia 2008 October; 40(5):273-81). Therapy with 5α-reductase inhibitors, such as finasteride, markedly reduces the DHT content of the prostate and, in turn, reduces prostate volume and, in many cases, BPH symptoms. Androgens are thought to be essential for BPH to occur, but do not seem to be the only cause for the condition.
Insulin-like growth factors(IGFs) and their binding proteins may play an important role in understanding the etiology of prostate disease, including BPH. Several lines of evidence support involvementof the IGF axis in BPH. IGF ligands have mitogenic effects on the prostate, while IGF binding proteins (IGFBPs) are growth inhibitory due to their ability to regulate availability of the IGFs, other growth factors, and steroid hormones (Pollak M N et al, Nat Rev 2004; 4:505-518.). IGFBP3 is secreted at particularly low levels in stromal cells in BPH tissue (Boudon C et al., J Clin Endocrinol Metab 1996; 81:612-617.) which may favor hyperplastic growth and play a role in the development of BPH. Moreover, acromegalic patients, who have very high levels of IGF1 and concomitantly low levels of testosterone and DHT, present with enlarged prostates and high rates of BPH (Colao A et al J Clin Endocrinol Metab 1999; 84:1986-1991; Colao A et al, Eur J Endocrinol 2000; 143:61-69.).
The insulin-like growth factor (IGF) system plays a key role in stimulating proliferation and survival of both normal tissues and cancers (reviewed in LeRoith D, Roberts C T Jr., Cancer Lett 2003; 195:127-37). High circulating IGF-1 concentrations have been associated with increased risk for prostate cancer in several clinical and epidemiologic studies (Price A J et al., Cancer Epidemiol Biomarkers Prev. 2012 September; 21(9):1531-41; Roddam A W et al., Ann Intern Med 2008; 149(7):461-71). In prostate epithelial cells, increased IGF-1 expression was shown to lead to higher rates of proliferation and/or lower rates of apoptosis (Takahara K et al., Prostate. 2011 April; 71(5):525-37). Loss of imprinting of the IGF-2 locus and increased expression of IGF-2 are observed in many cancers including prostate cancer (Jarrard D F et al., Clinical Cancer Research 1995; 1, 1471-1478.; Fu V X et al., Cancer Research 2008; 68, 6797-6802) and may be related to the risk to develop prostate cancer (Belharazem D et al, Endocrine Connections 2012; 1, 87-94). Furthermore, not only expression of IGF-1 and IGF-2 ligands but also their receptor, IGF-1R, has been shown to be elevated in advanced prostate tumors (Cardillo, M R et al., Anticancer Res. 2003 23, 3825-3835; Liao, Y et al., Hum. Pathol. 2005; 36 (11), 1186-1196; Hellawell G O et al., Cancer Res. 2002 May 15; 62(10):2942-50; Turney B W et al., BJU Int. 2011 May; 107(9):1488-99; Krueckl S L et al., Cancer Res. 2004 Dec. 1; 64(23):8620-9; Figueroa, J A et al., Cancer Invest. 2001; 19 (1), 28-34; Ryan, C J et al., Urol. Oncol. 2007; 25, 134-140). In recurrent and androgen-independent cancer, an increase also in AKT phosphorylation was demonstrated (Graff J R et al., J. Biol. Chem 2000; 275: 24500-5; Murillo H et al., Endocrinology 2001; 142: 4795-805.).
Castration-resistant prostate cancer has been shown to be sensitive, but not resistant, to sustained manipulation of the androgen/AR axis. The androgen axis can be manipulated using anti-androgens (nilutamide, enzalutamide), androgen synthesis inhibitors (ketonazole, abiraterone acetate), corticosteroids (dexamethasone, prednisone) or estrogen treatment. Following the emergence of castration-refractory disease, taxane-based chemotherapy has been shown to be therapeutically efficacious and prolong survival. Patients progressing on docetaxel have been shown to benefit from abiraterone acetate, a selective cytochrome P450 17A1 inhibitor which requires co-administration with glucocorticoids to curtail side effects. Enzalutamide (MDV-3100) is a novel AR antagonist that blocks AR signaling more effectively than currently available AR antagonists (Tran et al., Science 2009; 324(5928): 787-790.) and has shown impressive antitumor activity and a similar impact on overall survival as abiraterone.
Antagonists to IGF action and their use in cancer therapy have been described in the art. For disclosure of IGF receptor tyrosine kinase inhibitors, see WO2009/009016 and WO2010/099139. For disclosure of antibodies against IGF receptor, see WO2002/53596, WO2003/093317, WO2003/106621, WO2006/013472, WO2006/069202. For disclosure of antibodies against IGF ligand, see WO2003/093317, WO2005/028515, WO2007/022172, WO2007/070432, WO2008/155387, WO2009/137758, WO2010/066868. IGF-1 receptor antibodies, WO2008/098917, WO2009/137378) and IGF ligand antibodies (WO2007/118214, WO2008/155387, WO2009/137758, WO2010/066868) have been proposed for use, inter alia, in the treatment of prostate cancer.
The state of the art is also discussed in further publications (Pollak M N et al., Cancer Metastasis Rev 1998; 17:383-90; Djavan B et al., World J Urol 2001; 19:225-33; Wolk A et al., J Natl Cancer Inst 1998; 90:911-5; Jiang Y G et al., Int. J. Urol. 2007; 14:1034-9; Lin H K et al., Proc. Natl Acad. Sci. USA 2001; 98: 7200-5; Wen Y et al., Cancer Res. 2000; 60: 6841-5; Plymate S R et al., Prostate 2004; 61:276-90; A A Lubik et al., Endocr Relat Cancer ERC-12-0250 2013, first published on 14 January; Nickerson T et al. Cancer Res. 2001; 61 (16), 6276-6280; Pandini G et al., Cancer Res., 2005 Mar. 1; 65; 1849; Bedolla R et al. Clin Cancer Res. 2007 Jul. 1; 13(13):3860-7; Carver B S et al., Cancer Cell 2011 May 17; 19, 575-586; Mulholland D J et al., Cancer Cell, 2011 Jun. 14; 19, 792-804)
Despite advances made in the early detection and treatment of prostate neoplasia, including benign prostatic hyperplasia (BPH), prostate cancer, and particularly CRPC, there is a significant need for improvements in therapy.